The liver has the unique ability to regenerate after injury, but this may be insufficient for recovery under chronic stress. Unresolved liver injury may lead to conditions such as metabolic dysfunction–associated steatotic liver disease (MASLD), metabolic dysfunction–associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC). How hepatocytes become poised for tumorigenesis under these conditions, however, is not well-defined. To this end, Tzouanas, Shay, Sherman, and colleagues administered a high-fat diet (HFD) to mice as a mechanism of chronic stress and performed single-cell transcriptional and epigenetic profiling of HFD and control diet (CD) mice. HFD led to increased hepatocyte expression of genes that regulate cell survival, apoptosis, cholesterol biosynthesis, β-oxidation, and signal transduction, including WNT. These expression programs were even more enriched in the liver tumors that spontaneously arose in HFD mice. In contrast, HFD hepatocytes downregulated programs associated with lineage identity and homeostasis in addition to several metabolic genes, including 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), the rate-limiting enzyme for ketogenesis. Liver-specific Hmgcs2-knockout mice (LiverKO) fed a HFD had increased liver damage and circulating cholesterol. Single-nucleus RNA sequencing analysis of wild-type (WT) and LiverKO mice revealed high expression of hepatocyte stress response programs, developmental markers, and signaling proteins linked to HCC in the HFD LiverKO mice compared to mice fed a CD, to a much higher degree than that induced by a HFD in WT mice. These findings extended to publicly available human MASLD/HCC data. Similarly, there was concordance between transcriptional expression and epigenetic accessibility in mice and humans, with WNT signaling becoming dysregulated over time but not sufficient to drive tumorigenesis. To uncover causal factors regulating the hepatocyte stress response, Tzouanas and colleagues developed the MATCHA (Multi-omic Ascertainment of Transcriptional Causality via Hierarchical Association) algorithm, which uncovered several transcription factors linked to the programs downregulated with HFD for experimental validation. SOX4 and RELB exerted strong effects on metabolic stress-associated states, and their overexpression in vitro and in vivo recapitulated the outcomes seen with HFD in mice as well as the phenotypes of increased MASLD severity and worse HCC prognosis observed in humans. Taken together, these findings highlight how the cellular response to stress can potentiate cancer development.Tzouanas CN, Shay JES, Sherman MS, Rubin AJ, Mead BE, Dao TT, et al. Hepatic adaptation to chronic metabolic stress primes tumorigenesis. Cell 2026;189:435–60.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.
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